tbuckley/cabot-search huggingface dataset:
Characterizing the landscape of RING-type E3 ubiquitin transferase-altered (<i>RNF43 </i>alt) colorectal cancer (CRC) and defining unique subsets with potential therapeutic vulnerabilities in microsatellite instability-high (MSI-H) CRC.
Authors: Abdul Rafeh Naqash, Amin Nassar, Lisa Macera, Elizabeth Mauer, Justin Guinney, Calvin Y. Chao, Elio Adib, Emanuel Petricoin, Arjun Mittra, Naoko Takebe, Timothy Lewis Cannon
Journal: Journal of Clinical Oncology (2023)

3134 Background: RNF43 is a tumor suppressor gene that represses the WNT/β-catenin pathway. Emerging data show that RNF43 alt are commonly present in MSI-H CRC with improved outcomes to immune checkpoint inhibitors (ICI). We evaluated whether genomic and transcriptomic analysis of MSI-H RNF43 alt CRC defines distinct subsets with potential therapeutic vulnerabilities. Methods: We analyzed CRC tumors (any stage/ subtype) sequenced with Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). RNF43 alt were defined as pathogenic/likely pathogenic per OncoKB, or copy number aberrations (CNA); deep deletions, or amplifications (&gt;8x). RNF43 alt vs. wildtype (wt) were compared using Chi-squared/Fisher’s Exact tests or Wilcoxon rank-sum tests to evaluate differences in biomarkers. Gene Set Variation Analysis (GSVA) was applied to gene expression data to derive single-sample pathway enrichment scores. ICI-treated MSI-H CRC from the MSKCC cohort (n = 74), publicly available in AACR GENIE v13, was used to assess the overall survival (OS) using the Kaplan-Meier method. Results: RNF43 alt was identified in 5.2% (635 of 12,243) CRC tumors. CNA accounted for 6% of RNF43 alt CRC. RNF43 alt vs. RNF43 wt CRC was associated with older age (median 69 vs. 59 years, p &lt; 0.001), more prevalent in females (56% vs 43%; p &lt; 0.001). A detailed comparison of RNF43 alt vs. RNF43 wt CRC with p &lt; 0.001 are shown (Table). Of MSI-H CRC (n = 714), 51% were RNF43 alt, with 80% being RNF43 p.GLY659fs. Among MSI-H RNF43 alt CRC, BRAF alt was co-mutated in 59%, with BRAF V600E constituting 99%. Median TMB was higher for MSI-H RNF43 alt vs. MSI-H RNF43 wt (40 vs. 31 mut/MB, p &lt; 0.001). Among MSI-H CRC, GSVA identified significant downregulation of Cetuximab_benefit pathway and upregulation of IGF1R and PI3K/AKT pathways in RNF43 alt vs RNF43 wt. Among ICI-treated MSI-H CRC (n = 74) from the MSKCC cohort, no significant OS difference (HR 0.81 [95%CI: 0.34 – 1.97]; p = 0.65) was noted for RNF43 alt (n = 42) vs. wt (n = 32). Conclusions: RNF43 alt are common in MSI-H CRC and associated with potentially actionable genomic and transcriptomic signatures. Functional characterization of interplay between the WNT signaling and therapeutically relevant pathways (PI3K/AKT, BRAF, IGF1R, Cetuximab benefit) to better define optimal ICI combination approaches in MSI-H RNF43 alt CRC is ongoing. [Table: see text]
Safety, efficacy, and biomarker analysis of response to engineered tumor-infiltrating lymphocytes secreting anti-PD-1 antibody in recurrent glioblastoma: An open-label, two-arms, phase 1 study.
Authors: Yu Yao, Di Chen, Chao Tang, Chunxia Ji, Zhong Li, Qijun Qian
Journal: Journal of Clinical Oncology (2023)

2042 Background: Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) is effective against solid tumors with convincing evidence. But T-cells infused were exhausted when they encountered PD-1-mediated immunosuppression in the microenvironment. Here, we generated a modified autologous TILs secreting antibody targeting PD-1 (PD1-TIL), and conducted a first-in-human, two arms, phase 1 study (NCT03347097) in recurrent glioblastoma who had a poor prognosis with estimated 6-9 months of median overall survival (OS). Methods: Patients were included to be treated with PD1-TIL or TIL cell products intravenously every one month following surgery. The primary endpoint was safety and feasibility. The secondary endpoints were disease control rate (DCR), OS, immunologic responses and biomarker analysis. The clinical response to cell therapy was assessed by MRI according to iRANO criteria. Here, patients with clinical benefit (CR, PR, and SD) were defined as responder. Results: A total of 21 consecutive patients (median age 45 years, range 20–64) received infusions of cell products (7 patients for PD1-TIL with 1 excluded, 14 patients for TIL with 2 excluded). 52% (11/21) and 29% (6/21) of 21 patients had methylated MGMT promoter and IDH1/2 mutant respectively. No significant differences in baseline characteristics between groups were found. Both of PD1-TIL and TIL infusions were well tolerated with no unexpected high-grade adverse events. Of 7 evaluable patients in PD1-TIL group, 1 had PR for more than 26 months, 2 had SD lasting for 7.7 months and 24 months, and 4 had PD after infusion. The DCR, 1-year and 2-years survival rates in PD1-TIL group were 43% (3/7), 86% (6/7) and 29% (2/7) respectively. In TIL group, 3 patients had SD and the others had PD. The DCR, 1-year and 2-years survival rates in TIL group were half of that in PD1-TIL group. Survival analysis showed that patients treated by PD1-TIL had extended OS than those received TIL (16.1 vs. 11.2 months, P = 0.047). Among 21 patients, clinical responders had significantly improved OS (30.9 vs. 10.7 months, P = 0.001) than non-responders. We also found a high capacity for engraftment and persistence of infused TILs in peripheral blood which could be detectable at 6 months after treatment. Existence of neoantigen-reactive T cell clonotypes in cell products may be important for responding because missing of missense mutations predicted to generate a neoantigen after cell therapy was a remarkable signature in responders. Responsive tumors were also associated with tumor microenvironment profiles. Conclusions: This first-in-human study establish the preliminary feasibility, safety and encouraging efficacy of PD1-antibody-secreting TILs, and may constitute a new treatment strategy by T-cell genetic engineering in glioblastoma. Clinical trial information: NCT03347097 .
The incidence of thyroid-related adverse events in solid tumors receiving immune checkpoint blockade with curative intent: A meta-analysis.
Authors: Susu Zhou, Nobuyuki Horita, Theresa Shao, Matthew Harrington, Yu Fujiwara
Journal: Journal of Clinical Oncology (2023)

2641 Background: Adjuvant/neoadjuvant treatments with immune checkpoint blockade (ICB) improve survival outcomes in patients with several types of cancer. However, immune-related adverse events (irAEs) which frequently involve the thyroid gland may lead to delays in curative treatments such as surgery and radiotherapy. Thus, it is essential to report the incidence of thyroid-related adverse events (AEs) associated with the addition of ICB to conventional therapy with curative intent through a meta-analysis of randomized controls trials (RCTs). Methods: We performed a systematic search of PubMed, Embase, Web of Science, and Cochrane library for RCTs evaluating ICB-containing treatment of solid tumors with curative intent. We calculated the odds ratio (OR) of all-grade and grade 3-5 thyroid-related AEs including thyroiditis, hyperthyroidism, and hypothyroidism. We performed a meta-analysis using the random-effect model to compare the incidence of thyroid-related AEs in patients who received therapy with and without the addition of ICB. Subgroup analysis based on the type of ICB (anti-PD-1, anti-PD-L1, and anti-CTLA-4) was conducted. Results: 24 RCTs comprising 12,199 patients were analyzed. The addition of ICB was associated with higher incidence of all-grade thyroiditis (OR=3.53, 95%CI:1.88-6.64, p&lt;0.0001), hyperthyroidism (OR=7.18, 95%CI:4.30-12.01, p&lt;0.00001), and hypothyroidism (OR=5.39, 95%CI:3.68-7.90, p&lt;0.00001). In subgroup analysis, PD-1 and PD-L1 inhibitors were particularly associated with higher incidence of hyperthyroidism and hypothyroidism. The incidence of grade 3-5 thyroid-related AEs in patients who received therapy with the addition of ICB was 0.13% (thyroiditis, N=4/3135), 0.20% (hyperthyroidism, N=12/5877), and 0.19% (hypothyroidism, N=12/6369). Conclusions: The addition of ICB to conventional therapy with curative intent was associated with an increased risk of all-grade thyroid-related AEs, but the incidence of grade 3-5 AEs was low. These results suggest ICB may be added safely as an adjunct to curative treatments such as surgery and radiotherapy. Clinicians should monitor patients’ thyroid function and maintain vigilance for symptoms and signs of thyroid disease. OR (95% CI) and number of studies (N) for thyroid-related AEs with subgroup analysis. [Table: see text]
Autologous cytotoxic T-cell receptor T cell therapy (SCG101) against hepatitis B surface antigen phase I/II trial for patients with advanced hepatitis B-related hepatocellular carcinoma.
Authors: Ghassan K. Abou-Alfa, Wei-Peng Yong, Stephen Lam Chang, Jia Fan, Han Chong Toh, Thomas Yau, SuPin Choo, Jing Wang, Nicole Kusuma, Christy Ma, Shukui Qin
Journal: Journal of Clinical Oncology (2023)

TPS4181 Background: The overall prognosis of patients with advanced Hepatitis B-related hepatocellular carcinoma (HCC) remains poor, and treatment options are limited. In an IIT study conducted in China (NCT05339321), SCG101 following lymphodepletion (cy-flu) as second-line setting or beyond in patients with Hep B-related HCC has shown acceptable safety profile, reduction in HBsAg levels (&gt;1 log) and tumor control. A phase I/II trial has been initiated to evaluate safety and RP2D of autologous SCG101 T cell therapy in Hepatitis B virus-related HCC (NCT05417932). Methods: This multicenter, open-label, 3+3 dose-escalation phase I trial is ongoing across 7 sites in the United States, Singapore and Hong Kong SAR, and a parallel study is done in mainland China across 8 sites. Eligible patients have a histologically confirmed HCC, not amenable to curative intent (surgery or locoregional therapy) and failed ≥2 standard line of therapies, match any of HLA-A*02:01, *02:02, *02:03, *02:04, *02:07, *02:09,*02:16, have positive serum (or tumor) HBsAg, HBV-DNA &lt;2000 IU/ml, BCLC B or C, CP≤7, with measurable disease at screening (mRECIST and RECIST v1.1), ECOG PS&lt;1. Patients with CNS metastasis, prior liver transplant, autoimmune disease or prior cell therapy are excluded. SCG101 T cells is manufactured in Singapore under cGMP and ship to all study sites across the U.S, Singapore and Hong Kong SAR, while SCG101 T cells for the China sites is manufactured in SCG Cell Therapy’s China facility. Patients will receive a single dose of SCG101 T cell therapy following lymphodepletion (cy-flu). Endpoints include safety, MTD and RP2D. Secondary endpoints include ORR, DOR, PFS, OS, changes in serum HBsAg. Safety is monitored together with Data Review Committee. The study is actively enrolling, and the phase II portion of the trial is expected to be initiated by H2 2023. Autologous SCG101 T cell therapy may provide a new treatment option for patients with advanced Hepatitis B virus-related HCC. Clinical trial information: NCT05417932 .
A first-in-human study of MIL95, an anti-CD47 monoclonal antibody (mAb), in patients with advanced solid tumors and lymphomas.
Authors: Qingyuan Zhang, Aiguo Liu, Jianhua Shi, Qingqing Cai, Zerui Qu, Sijun Liu, Yuqin Song
Journal: Journal of Clinical Oncology (2023)

e14513 Background: CD47 provides a potent “do not eat me” signal that allows the tumor to escape removal by the innate immune system. MIL95 is a humanized, anti-CD47 lgG4 monoclonal antibody and that mediated blockade of CD47 can induce macrophage phagocytosis of cancer cells. To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of MIL95, we conducted a first-in-human phase 1 trial in pts with advanced solid tumors and lymphomas (Protocol number MIL95-CT101, Beijing Mabworks Biotech Co. Ltd.) at 5 clinical study sites in China. Currently the study is still ongoing. Methods: We enrolled pts aged 18 years or older with advanced solid tumors and lymphomas whose disease had progressed after standard systemic treatments. Pts were required to ECOG PS score of 0-1 and adequate organ functions. Pts were enrolled in this two-part dose-escalation study: Part A, to determine a priming dose at 0.1, 0.3, 0.8, 1 mg/kg; Part B, to determine optimal weekly maintenance dose at 3, 10, 20, 30, 45 mg/kg. Dose escalation was performed using an accelerated titration followed by traditional 3+3 design during a 14-day (Part A) or 28-day (Part B) dose-limiting toxicity (DLT) observation period. Results: As of 18 Dec 2022, 24 pts (median age 54.5 years; 37.5% male; 54.2% ECOG PS 1) were treated: 8 in part A, 16 in part B. The common tumor types were lymphomas (25.0%) and breast (25.0%), lung (12.5%) cancers. MIL95 toxicity was manageable, no DLT was observed, and dose escalation was ongoing at 45mg/kg. The most common treatment-related adverse events (TRAEs) occurring in ≥10% of pts were anemia (37.5%), blood bilirubin increased (37.5%), leukopenia (20.8%), pyrexia (16.7%), and fatigue (16.7%). Most toxicities were Grade 1 or 2. Five pts had ≥Grade 3 TRAEs (Grade 3 anemia in 2 pts, Grade 3 decreased appetite in 1 pt, Grade 3 enteritis infectious in 1 pt, Grade 4 platelet count decreased in 1 pt). 4 pts had SD as a best response, with 1 pt (Cholangiocarcinoma at dose 20 mg/kg) on study for &gt;5 months. Conclusions: MIL95 was well tolerated at 1 mg/kg priming dose following by maintenance doses of up to 45 mg/kg weekly. Further antitumor activity may need to be combined with other therapies. Clinical trial information: NCT04651348 .
Mutational profiling of newly diagnosed glioblastoma to identify predictive biomarkers of efficacy and safety of anlotinib combination therapy.
Authors: Shuzhen Lai, Peijing Li, Xiaohui Liu, Guihong Liu, Tieming Xie, Xing Zhang, Xiaoxuan Wang, Jing Huang, Yiqiang Tang, Zhigang Liu, Guoping Shen, Chaoming Li, Fangxiao Lu, Lei Wang, Fagui Jiang, Caixing Sun, Yuan yuan Yuan Chen
Journal: Journal of Clinical Oncology (2023)

e14037 Background: Glioblastoma (GBM) is highly vascular tumor with the specific pathologic feature of microvascular proliferation. Our previous phase Ⅱ clinical trial (NCT04119674) has firstly demonstrated the antiangiogenic multikinase inhibitor anlotinib combined with STUPP regimen can lengthen progression-free survival (PFS) in patients with newly diagnosed GBM. However, no biomarker for angiogenic therapy has been proved yet. Therefore, the second analysis was performed to identify the predictive biomarkers. Methods: A total of 21 patients with newly diagnosed GBM were enrolled in the retrospective research. The methylation status of the MGMT gene promoter was examined using the MDxHealth PCR assay. DNA-based whole genome sequencing was undertaken to detect the genomic alterations of patients. Results: The differences of gene aberrances between patients who reached and those who did not reach the primary endpoint were observed. ATRX and MYO15A mutations were only found in patients who had yet not experienced relapse. On contrast, the mutations of PIK3CA, HEG1, HMCN1 and RP1L1 occurred only in the recurrent group. HEG1 (HR 6.0, 95% CI 1.2-28.8, p= 0.026) and RP1L1 (HR 12.5, 95% CI 2.1-74.3, p= 0.005), genes related to angiogenesis, were both independent biomarkers of PFS. RP1L1 was also significantly associated with shorter overall survival (OS) (HR 33.4, 95% CI 3.2-351.4, p= 0.003). Interestingly, PIK3CA alterations were significantly higher in patients with cerebral than in those without ( p= 0.032, OR 16.4). Conclusions: Our study suggested that alterations in HEG1, RP1L1 and PIK3CA could be novel biomarkers for the newly diagnosed GBM patients received anti-angiogenesis combination therapy, and provided now insights for the precise treatment of GBM.
Evaluating the effectiveness and tolerability of chemotherapy in hairy cell leukemia: A comprehensive systematic review and meta-analysis.
Authors: Jawad Basit, Zaofashan Zaheer, Aleena Ahmed, Maurish Fatima, Usman Ali Akbar, Nithya Ramesh, Asna Shahab, Mohammad Ebad Ur Rehman, Zunairah Shah, Sajeel Saeed, Mahboob Ahmad, Azka Aisha
Journal: Journal of Clinical Oncology (2023)

e19547 Background: Hairy cell leukaemia (HCL) is a rare, chronic B cell cancer that involves the bone marrow, peripheral blood, and spleen. Many treatment options are available for HCL. Our study aims to elucidate the safety and efficacy of each intervention through the pooled proportion of response to treatment and adverse events. Methods: We conducted a literature search across PubMed, Embase, Cochrane, and Google Scholar from inception till February 2023. We included clinical trials and cohorts of patients with HCL receiving modern anticancer drugs (cladribine, rituximab, cladribine plus rituximab, BRAF inhibitors, anti-CD22 monoclonal antibodies, and ibrutinib). The primary efficacy outcomes were Objective Response Rate (ORR) and Complete Response Rate (CRR) and the primary safety outcome was adverse effects (AEs). We used OpenMetaAnalyst to pool data using the Hedges-Olkin Random Effects Model, with subgroup analysis for HCL type and study design. Results: Our meta-analysis included 44 studies (28 trials and 16 cohorts) with 3976 patients with HCL. The median age was 56.7 years. The highest efficacy was seen in patients receiving combination therapy of cladribine and rituximab, with an ORR of 97% and CRR of 92%. Cladribine monotherapy showed an ORR of 95% and CRR of 79%, while rituximab monotherapy had an ORR of 62% and CRR of 31%. BRAF inhibitors, anti-CD22 monoclonal antibodies, and ibrutinib showed less efficacy, with ORRs of 92%,78% and 51% and CRRs of 41%, 49%, and 17% respectively. Subgroup analysis for study design and HCL type did not resolve heterogeneity. The ORR and CRR with 95% Confidence Intervals and AEs for each regimen are given in the table. Conclusions: Cladribine with rituximab is the most effective treatment for untreated and relapsed HCL patients, with neutropenia as the most common AE. Since we pooled the proportions for treatment-naïve and relapsed cases together due to inavailability of segregated data, the results should be used cautiously in clinical decision making and limit the derivation of consensus for treatment of newly diagnosed or relapsed HCL. [Table: see text]
Disitamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate (ADC), combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma: An open-label phase 1b/2 study.
Authors: Xinan Sheng, Li Zhou, Kaiwei Yang, Shun Zhang, Huayan Xu, Xieqiao Yan, Siming Li, Juan Li, Chuanliang Cui, Zhihong Chi, Lu Si, Bixia Tang, Lili Mao, Bin Lian, Xuan Wang, Xue Bai, Zhisong He, Hongqian Guo, Jun Guo
Journal: Journal of Clinical Oncology (2023)

4566 Background: Disitamab vedotin has shown promising data across a spectrum of HER2 expression in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who progressed on chemotherapy. This study was conducted to evaluate the safety and efficacy of disitamab vedotin plus anti-PD-1 antibody in advanced urothelial carcinoma. Methods: This is an open-label, multicenter, phase 1b/2 trial to evaluate the safety and activity of RC48-ADC combined with toripalimab, a humanized immunoglobin G 4 monoclonal antibody against PD-1 in mUC. Patients received RC48-ADC at 1.5 or 2 mg/kg, in combination with 3mg/kg toripalimab every two weeks in a dose-escalation and expansion cohort until confirmed disease progression assessed by the investigators, unacceptable toxicity, or voluntary withdrawal. The primary endpoint was safety; secondary endpoints included efficacy and tumor tissue biomarkers. Results: Forty-one la/mUC patients were enrolled (22 males; median age 66 y [42-76]; 61% treatment-naïve). 54% of patients had visceral metastases (mets), including 24% with liver mets. The primary site was in upper tract UC in 54%. HER2 expression IHC 2+ or 3+ was in 59% patients, and PD-L1 positive in 32%. No dose-limiting toxicity was observed and the recommended dose was RC48-ADC 2mg/kg plus toripalimab 3mg/kg every two weeks. By the cutoff date of 18 November 2022, the confirmed ORR was 73.2% (95%CI: 57.1, 85.8), including 9.8% CR. The ORR was 76.0% for treatment-naïve patients. In HER2 IHC 3+/2+, IHC 1+, and IHC 0 subgroups, the ORR was 83.3%, 64.3%, and 33.3%, respectively. The ORR was 61.5% and 78.6% in PD-L1 positive and negative subgroups. DCR was 90.2% (95% CI, 76.9–97.3), with a median progression-free survival (PFS) of 9.2 months (95%CI: 5.7-10.3) and 2-year overall survival (OS) rate of 63.2%. All patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were AST/ALT increase (68.3%), peripheral sensory neuropathy (61.0%), asthenia (61.0%), γ-glutamyl transferase increase (56.1%), hypertriglyceridemia (53.7%), and appetite decrease (51.2%). Grade 3 or greater TRAEs occurred in 43.9% of patients. Twenty-three patients (56.1%) had immune-related AEs (14.6% ≥ G3), including immune-related skin reactions, hyperglycemia, pneumonitis, hepatitis, and myositis. Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in patients with la/mUC and a manageable safety profile. A phase 3 study is currently ongoing to compare the safety and efficacy of this regimen with standard of care. Clinical trial information: NCT04264936 .
Dose optimization of novel BRAF inhibitor FORE8394 based on PK and efficacy results.
Authors: Eric Jeffrey Sherman, Macarena Ines De La Fuente, Rona Yaeger, Frank Yung-Chin Tsai, Filip Janku, Nicholas A. Butowski, Carl E. Allen, Natraj Reddy Ammakkanavar, Jennie Webster Taylor, Emil Samara, Diane R. Mould, Glenn Michelson, Irina Kline, Michael Paz, Alexia Tussay-Lindenberg, Kongming Wong, Stacie Peacock Shepherd, Ping Jiang, Jordi Rodon Ahnert
Journal: Journal of Clinical Oncology (2023)

3106 Background: FORE8394 is a selective inhibitor of class 1 (V600) and 2 (activating non-V600) BRAF alterations that avoids paradoxical MAPK pathway activation. Consistent with the paradigm shift to optimal dosing vs identifying the maximal tolerated dose, integrated pharmacokinetic (PK), genomics, safety, and efficacy data, and exposure-response modeling were used to identify the recommended dose (RD). Methods: In a single arm phase 1/2a study, patients (pts) age ≥3 years with advanced solid or CNS tumors with BRAF alterations received FORE8394 900-3600 mg/day with or without the PK enhancer cobicistat (cobi) until progression. Efficacy pts had class 1 or 2 BRAF alterations &amp; ≥1 post-baseline assessment (mITT); the BRAF V600 MAPKi naïve, non CRC subset provided a homogenous subset to also inform dose selection. PK was evaluated after single and repeated dosing. Results: To date, 110 pts (age range 4-86 years) received ≥1 dose of FORE8394; 58% had ≥2 prior lines of therapy, 25% had prior MAPKi. PK was independent of age or weight. Cobi increased FORE8394 exposure 2-3-fold. Exposure increased with dose, with less than proportional increase at doses &gt;900 mg BID. Higher Cmax and trough levels were achieved with QD vs BID/TID. Objective (confirmed) responses were observed at all doses; however, objective response rate (ORR) was greatest (50%) at 900mg QD + cobi, with no further increases in ORR at higher doses. Dose-limiting toxicities were only observed at doses ≥1500 mg/day + cobi: 1500-1800 mg/day (4) and 2700-3600 mg/day (1). Similarly, treatment-emergent adverse events (TEAEs) ≥Grade 3 (G3) increased at the higher doses. Only 1 pt discontinued FORE8394 due to treatment-related AE (G3 bilirubin; 3600 mg/day). Conclusions: Based on the entirety of safety, PK, and efficacy data, the optimal RD of FORE8394 in Phase 2 is 900 mg QD + cobi in pts ≥10 years old. This achieved targeted efficacious exposures with robust antitumor activity and favorable safety. This dose optimization is consistent with current guidelines, avoids higher exposure that may lead to higher toxicity and compromise dose intensity. QD dosing also allows for a convenient dosing regimen. A Phase 2 study at the RD is ongoing in pts with recurrent V600E BRAF-mutated primary CNS tumors and advanced solid or CNS tumors with BRAF fusions. Clinical trial information: NCT02428712 . [Table: see text]